Triheptanoin for glucose transporter type I deficiency (G1D): modulation of human ictogenesis, cerebral metabolic rate, and cognitive indices by a food supplement

Abstract

Importance: Disorders of brain metabolism are multiform in their mechanisms and manifestations, many of which remain insufficiently understood and are thus similarly treated. Glucose transporter type I deficiency (G1D) is commonly associated with seizures and with electrographic spike-waves. The G1D syndrome has long been attributed to energy (ie, adenosine triphosphate synthetic) failure such as that consequent to tricarboxylic acid (TCA) cycle intermediate depletion. Indeed, glucose and other substrates generate TCAs via anaplerosis. However, TCAs are preserved in murine G1D, rendering energy-failure inferences premature and suggesting a different hypothesis, also grounded on our work, that consumption of alternate TCA precursors is stimulated and may be detrimental. Second, common ketogenic diets lead to a therapeutically counterintuitive reduction in blood glucose available to the G1D brain and prove ineffective in one-third of patients.

Objective: To identify the most helpful outcomes for treatment evaluation and to uphold (rather than diminish) blood glucose concentration and stimulate the TCA cycle, including anaplerosis, in G1D using the medium-chain, food-grade triglyceride triheptanoin.

Design, setting, and participants: Unsponsored, open-label cases series conducted in an academic setting. Fourteen children and adults with G1D who were not receiving a ketogenic diet were selected on a first-come, first-enrolled basis.

Intervention: Supplementation of the regular diet with food-grade triheptanoin.

Main outcomes and measures: First, we show that, regardless of electroencephalographic spike-waves, most seizures are rarely visible, such that perceptions by patients or others are inadequate for treatment evaluation. Thus, we used quantitative electroencephalographic, neuropsychological, blood analytical, and magnetic resonance imaging cerebral metabolic rate measurements.

Results: One participant (7%) did not manifest spike-waves; however, spike-waves promptly decreased by 70% (P = .001) in the other participants after consumption of triheptanoin. In addition, the neuropsychological performance and cerebral metabolic rate increased in most patients. Eleven patients (78%) had no adverse effects after prolonged use of triheptanoin. Three patients (21%) experienced gastrointestinal symptoms, and 1 (7%) discontinued the use of triheptanoin.

Conclusions and relevance: Triheptanoin can favorably influence cardinal aspects of neural function in G1D. In addition, our outcome measures constitute an important framework for the evaluation of therapies for encephalopathies associated with impaired intermediary metabolism.

Figure 1. Metabolism of glucose, C7-derived heptanoate and 5-carbon (C5) ketones in the brain

Glial metabolism is distinct from neuronal metabolism. Glucose can access both glia (via GLUT1) and neurons (via GLUT3), fueling the TCA cycle (CAC). In glia, pyruvate is converted into oxaloacetate (OAA) via carboxylation, donating net carbon to the TCA cycle (anaplerosis). This reaction can be impaired in G1D. Like glucose, the C7 derivative heptanoate and related metabolites (i.e., the 5-carbon ketones beta-ketopentanoate and beta-hydroxypentanoate) also generate acetyl-coenzyme A (Ac-CoA) but, unlike the 4-carbon ketone bodies beta-hydroxybutyrate and acetoacetate, they can also be incorporated into succinyl-coenzyme A (Suc-CoA) via propionyl-CoA (Prop-CoA) formation, supplying net, anaplerotic carbon to the cycle. In addition to 5-carbon (C5) ketones, the 4-carbon ketone bodies beta-hydroxybutyrate and acetoacetate are also metabolites of C7.

Figure 2. Flow diagram of study visits and procedures

Each subject participated in 3 visits: Screening/baseline (initiation of triheptanoin supplementation), 3 month follow-up (discontinuation of triheptanoin supplementation), and 6 month follow up (study exit).

Figure 3. EEG-captured spike-wave seizures in G1D patients

(a) An example segment of EEG recording containing three spike-wave seizure periods. Electrode position followed standard abbreviated nomenclature. Vertical bars: 1 s. (b) Illustration of the identification of seizure duration. (c) The seizure-nonseizure binarized time course of a representative subject: Spike-wave periods are represented as bar plots against EEG time course in the setting of a non-seizure baseline state. Triheptanoin (oil) administration is marked as a pink bar in (c).

Figure 4. Seizure rate reduction after acute triheptanoin oil consumption

(a) Seizure rate of each subject pre- and post-triheptanoin oil consumption. (b) Rank-transformed seizure rate of each subject pre- and post-triheptanoin oil consumption.

Figure 5. Neuropsychological indices in G1D patients after triheptanoin food supplementation

Vocabulary performance improved acutely and long term with triheptanoin supplementation. The neuropsychological scores of all 8 G1D subjects before and after triheptanoin are represented. Subject designations are the same through all the figures and tables. Standardized PPVT and EVT ratings (y-axis) were obtained in the fasting state (baseline) at time 0 min (x-axis 1A suffix) and 60 min (x-axis 1B suffix) following triheptanoin ingestion, and then subsequently after 3 months of daily triheptanoin supplementation (x-axis T2 suffix). PPVT and EVT scores were below normal age ranges and increased at subsequent time points in rigorously statistically significant fashion. The 95% confidence intervals for the PPVT scaled scores at each of the three time points studies were 54.4 - 76.3; 63.6 - 82.9 and 60.4 - 87.6, respectively. PPVT scores improved significantly over time (F_2,14 = 5.945, p=0.014), although there were no significant pairwise comparisons after Bonferroni adjustment for multiple comparisons. The 95% confidence intervals for the EVT scaled scores at each of the three time points studies were 56.6 - 77.2; 59.4 - 81.3 and 67.6 - 86.6, respectively. EVT scores improved significantly over time (F_2,14 = 9.571, p=0.002). Pairwise comparisons yielded (pre-oil relative to follow-up) p=0.006 (Bonferroni adjustment for multiple comparisons).

Figure 6. MRI-measured CMRO2 of each subject pre- and post- acute triheptanoin oil consumption

In subjects GD009 and GD007, CMRO2 was measured again at 5-6 months post-triheptanoin oil consumption. The normal values for CMRO2 have been measured by us in a broad adult age-range and are gender-dependent (i.e., females exhibit higher CMRO2 than males). At ages 21 and 28 years, the normal male CMRO2 is 149 and 154 µmol/100g/min, respectively. The standard deviation none of our normal CMRO2 measurements exceeds 12.5 µmol/100g/min (HL et al, Age-related increase of resting metabolic rate in the human brain; submitted).